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2016 ; 16
(ä): 92
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A review of clinical trial designs used to detect a disease-modifying effect of
drug therapy in Alzheimer s disease and Parkinson s disease
#MMPMID27312378
McGhee DJ
; Ritchie CW
; Zajicek JP
; Counsell CE
BMC Neurol
2016[Jun]; 16
(ä): 92
PMID27312378
show ga
BACKGROUND: Disease-modification clinical trials in neurodegenerative disorders
have struggled to separate symptomatic effects of putative agents from
disease-modification. In response, a variety of clinical trial designs have been
developed. A systematic review was undertaken to examine which trial designs have
been used in Alzheimer's disease (AD) and Parkinson's disease (PD) to detect
disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed
to identify novel clinical trial designs used in the past or planned for use in
the future. We aimed to critique whether the methods used would have identified
true disease-modification. METHODS: MEDLINE, Embase and CENTRAL (1980-2015) were
searched to identify papers meriting review in full. ClinicalTrials.gov was
searched to identify unpublished or planned randomised controlled trials (RCTs).
We included RCTs in PD or AD which aimed to demonstrate the disease-modifying
properties of drug therapy and differentiate that benefit from any symptomatic
effect. RESULTS: 128 RCTs were finally included: 84 in AD (59 published, 25
unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial
designs were applied including long-term follow-up, wash-in and wash-out
analyses, randomised delayed-start, the use of time-to-event outcome measures and
surrogate disease progression biomarkers. Deficiencies in each of these design
strategies, the quantity of missing data in included RCTs and the methods used to
deal with missing data, meant that none of the included studies convincingly
demonstrated disease-modification. No truly novel clinical trial designs were
identified. CONCLUSION: We currently believe that the best clinical trial design
available to demonstrate disease-modification is a long-term follow-up study, in
which an examination is made for sustained divergence in outcome measures between
treatment arms over the study period.